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Publication numberUS20030059454 A1
Publication typeApplication
Application numberUS 10/252,848
Publication dateMar 27, 2003
Filing dateSep 24, 2002
Priority dateSep 24, 2001
Also published asCA2458828A1, DE60238422D1, EP1429819A1, EP1429819B1, US6908622, US7906133, US20050202061, WO2003035135A1
Publication number10252848, 252848, US 2003/0059454 A1, US 2003/059454 A1, US 20030059454 A1, US 20030059454A1, US 2003059454 A1, US 2003059454A1, US-A1-20030059454, US-A1-2003059454, US2003/0059454A1, US2003/059454A1, US20030059454 A1, US20030059454A1, US2003059454 A1, US2003059454A1
InventorsJames Barry, Kalpana Kamath
Original AssigneeBarry James J., Kamath Kalpana R.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Optimized dosing for drug coated stents
US 20030059454 A1
Abstract
The inventors have found that both the drug dose and drug release profiles are significant factors for the safety and efficacy of drug coated stents. The inventors have identified optimum dosing and release kinetics for drug coated stents. In particular, the inventors have determined dosing and release kinetics that permit the delivery of the lowest effective drug dosage, thus enhancing patient safety and minimizing any side effects from the drug.
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Claims(29)
What is claimed is:
1. A drug coated stent comprising:
a structural member insertable into a body lumen of a patient; and
a drug coated onto at least a portion of said structural member;
wherein said drug is released from said stent into the patient for a time period of at least eight days after insertion into the patient.
2. The drug coated stent of claim 1, wherein said drug is released from said stent into the patient for a time period of at least ten days after insertion into the patient.
3. The drug coated stent of claim 1, wherein said drug comprises paclitaxel.
4. The drug coated stent of claim 1, wherein said drug is incorporated into a polymer carrier coated onto at least a portion of said structural member.
5. The drug coated stent of claim 4, wherein said polymer comprises styrene.
6. A drug coated stent comprising:
a structural member insertable into a body lumen of a patient; and
a drug coated onto at least a portion of said structural member;
wherein said drug is released from said stent at a varying rate over time, said rate being maximized between one and three days after insertion into the patient.
7. The drug coated stent of claim 6, wherein said rate is maximized at approximately two days after insertion into the patient.
8. The drug coated stent of claim 6, wherein said drug comprises paclitaxel.
9. The drug coated stent of claim 6, wherein said drug is incorporated into a polymer carrier coated onto at least a portion of said structural member.
10. The drug coated stent of claim 9, wherein said polymer comprises styrene.
11. A paclitaxel coated stent comprising:
a structural member insertable into a body lumen of a patient; and
paclitaxel coated onto at least a portion of said structural member;
wherein less than about 60 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
12. The paclitaxel coated stent of claim 11, wherein less than about 20 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
13. The paclitaxel coated stent of claim 11, wherein less than about 15 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
14. The paclitaxel coated stent of claim 11, wherein less than about 10 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
15. The paclitaxel coated stent of claim 11, wherein less than about 8 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
16. The paclitaxel coated stent of claim 11, wherein less than about 6 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
17. The paclitaxel coated stent of claim 11, wherein less than about 4 micrograms of paclitaxel is released from said stent ten days after exposure to an aqueous environment.
18. The paclitaxel coated stent of claim 11, wherein said drug is incorporated into a polymer carrier coated onto at least a portion of said structural member.
19. The drug coated stent of claim 18, wherein said polymer comprises styrene.
20. A paclitaxel coated stent comprising:
a structural member insertable into a body lumen of a patient; and
paclitaxel coated onto at least a portion of said structural member;
wherein less than about 10 micrograms of paclitaxel is released from said stent two days after exposure to an aqueous environment.
21. The paclitaxel coated stent of claim 20, wherein less than about 5 micrograms of paclitaxel is released from said stent two days after exposure to an aqueous environment.
22. The paclitaxel coated stent of claim 20, wherein less than about 2 micrograms of paclitaxel is released from said stent two days after exposure to an aqueous environment.
23. A stent coated with paclitaxel, said paclitaxel having a dosage of up to about 2 micrograms per square millimeter of the stent surface area.
24. The stent of claim 23, wherein said dosage is up to about 1 microgram per square millimeter of the stent surface area.
25. The stent of claim 23, wherein the paclitaxel is incorporated into a polymer carrier coated onto at least a portion of the stent.
26. The stent of claim 25, wherein the polymer comprises styrene.
27. The stent of claim 23, wherein the weight fraction of the paclitaxel in the polymer carrier is less than about 35 percent.
28. The stent of claim 23, wherein said dosage is up to about 1 microgram per square millimeter of the stent surface area, and the weight fraction of the paclitaxel in the polymer carrier is less than about 25 percent.
29. The stent of claim 23, wherein said dosage is up to about 1 microgram per square millimeter of the stent surface area, and the weight fraction of the paclitaxel in the polymer carrier is less than about 8.8 percent.
Description
    FIELD OF THE INVENTION
  • [0001]
    The present invention relates to optimized biological responses as a function of dosage and release kinetics of drugs from implantable medical devices.
  • BACKGROUND OF THE INVENTION
  • [0002]
    Stents are tubular scaffold structures used to prop open blood vessels and other body lumens. The most widespread use of stents is to open clogged coronary arteries and prevent restenosis. The use of stents coated with therapeutic agents has been proposed to help minimize the possibility of restenosis. For example, stents coated with paclitaxel have been shown to reduce restenosis rates when compared with uncoated stents.
  • [0003]
    Although a number of drug coated stents have been reported, there has been a lack of published information regarding the optimization of drug dosing and drug release kinetics to address safety and efficacy. There is thus a need to identify, for a given coated stent system, the effective therapeutic window based on the selection of an appropriate drug dose to obtain a desired biological response.
  • SUMMARY OF THE INVENTION
  • [0004]
    The inventors have identified preferred drug dosing and drug release profiles for the safety and efficacy of drug coated stents. The embodiments described herein are specific to metallic stents coated with paclitaxel in a polymeric carrier, but the invention is thought to be applicable to stents coated with other drugs, with or without a polymeric carrier.
  • [0005]
    In one embodiment, the invention includes a drug coated stent comprising a structural member insertable into a body lumen of a patient, and a drug coated onto at least a portion of the said structural member. The drug is released from the stent into the patient for a time period of at least eight days after insertion into the patient.
  • [0006]
    In another embodiment, the invention includes a drug coated stent, where the drug is released from the stent at a varying rate over time. The rate is preferably maximized between one and three days after insertion into the patient.
  • [0007]
    In another embodiment, the invention includes a paclitaxel coated stent wherein after ten days following insertion into a patient, only less than about 60 micrograms of paclitaxel is released from the stent.
  • [0008]
    In another embodiment, the invention includes a paclitaxel coated stent wherein after two days following insertion into a patient, only less than about 10 micrograms of paclitaxel is released from the stent.
  • [0009]
    In another embodiment, the invention includes a paclitaxel coated stent having a dosage of up to about 2 micrograms per square millimeter of the stent surface area.
  • [0010]
    In yet another embodiment, the invention includes a paclitaxel coated stent, wherein the paclitaxel is included in a polymer carrier and the weight fraction of the paclitaxel in the polymer carrier is less than about 35 percent.
  • DESCRIPTION OF THE DRAWINGS
  • [0011]
    [0011]FIG. 1 shows histology results from a porcine dosing study.
  • [0012]
    [0012]FIGS. 2a-2 c illustrate the difference in biological response resulting from the difference in release rate from a paclitaxel coated stent.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0013]
    The inventors have found that both the drug dose and drug release profiles are significant factors for the safety and efficacy of drug coated stents. The inventors have identified optimum dosing and release kinetics for drug coated stents. In particular, the inventors have determined dosing and release kinetics that permit the delivery of the lowest effective drug dosage, thus enhancing patient safety and minimizing any side effects from the drug.
  • [0014]
    In a preferred embodiment of the present invention, the drug for coating a stent is paclitaxel. Other drugs that may be useful for treating diseases such as restenosis include known anti-inflammatory, anti-thrombogenic, anti-angiogenic, matrix production inhibatory, anti-migratory, cytostatic, and/or cytotoxic agents. Drugs currently being used or considered as stent coating materials to combat restenosis include paclitaxel, sirolimus, tacrolimus, and everolimus. The present invention is thought to be applicable to any of these restenosis inhibiting drugs.
  • [0015]
    In another preferred embodiment, the drug paclitaxel is contained in a polymer coating applied to a metallic stent. In certain embodiments, the polymer coating is a styrene-isobutylene based block copolymer, olefin polymer, polyethylene, polypropylene, polyvinyl chloride, polytetrafluoroethylene, fluorinated ethylene propylene copolymer, polyvinyl acetate, polystyrene, poly(ethylene teraphthalate), polyurethane, polyurea, silicone rubbers, polyamides, polycarbonates, polyaldehydes, natural rubbers, polyester copolymers, styrene-butadiene copolymers ethylene vinyl acetate, polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, polycaprolactone (PCL), poly-DL-lactic acid (DL-PLA) or poly-L-lactic acid (L-PLA), lactide, polyphosphazenes polyethylene oxide or polyethylene teraphtholate (PET), polybutylene teraphtholate (PBT), PEBAX, Nylon, or polycaprolactone, polyorthoesters, polylactic acids, polyglycolic acids, albumin or combinations of any of the above. In a most preferred embodiment, the polymer is a styrene-based polymer.
  • [0016]
    Paclitaxel coated metallic stents of various doses were implanted into healthy porcine arteries to determine the effect of dosage on biological response. Dosages used were approximately 4.0, 2.0, 1.0, and 0.6 micrograms per square millimeter of the stent surface area, corresponding to approximate total dosages of 345, 175, 85, and 50 micrograms per stent. The paclitaxel was contained within a styrene-isobutylene based block copolymer applied to the stent struts. As can be seen in FIG. 1a, the highest dose (i.e. 4.0 micrograms/mm2) resulted in a pronounced vessel relaxation, fibrin accumulation, medial thinning, loss of endothelial cells, and possible thrombus formation.
  • [0017]
    As the dose is decreased, the adverse effects described for the 4.0 micrograms/mm2 dose are minimized. At 2.0, 1.0, and 0.6 micrograms/mm2, there is a corresponding decrease in the effects of paclitaxel, such that endothelial cell loss, medial thinning, fibrin accumulation, and possible thrombus formation are all minimized. Based on these results, the preferred paclitaxel dosage is up to about 2.0 micrograms/mm2, more preferably less than about 1.5 micrograms/mm2, and most preferably up to about 1.0 micrograms/mm2.
  • [0018]
    In particular embodiments, the dosage is 0.4 to 2.0 micrograms/mm2, 0.7 to 1.5 micrograms/mm2, or 1.0 to 1.3 micrograms/mm2. In other embodiments, the dosage is 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 micrograms/mm2.
  • [0019]
    Using the 1.0 micrograms/mm2 dose as an exemplary embodiment, the effects of release rate were investigated. Metallic stents were coated with paclitaxel in a styrene-isobutylene based block copolymer carrier with the weight percent of paclitaxel in the carrier varying from approximately 8.8 to about 35%. The dose of drug applied to the stents was kept at 1.0 micrograms/mm2, and the total drug dose was held constant by varying total coating weight. The results shown in FIG. 2, as determined from in vitro release studies involving an aqueous environment, illustrate that the different weight fractions of paclitaxel in the polymer carrier resulted in different release kinetics.
  • [0020]
    In particular embodiments, the weight percent of paclitaxel in the carrier or polymer coating is 5% to 35%, 10% to 30%, 15% to 25%, or 18% to 22%.
  • [0021]
    As can be seen from FIG. 2, there was a direct correlation between drug weight fraction in the carrier and the release rate. For example, the highest weight fraction tested (35%) resulted in the release of approximately 45 micrograms of paclitaxel within two days after implantation. In contrast, the lowest weight fraction tested (8.8%) resulted in the release of only about 2 micrograms of paclitaxel within the same time period. The fastest release rate (FIG. 2a) resulted in noticeable fibrin accumulation, whereas slower rates (FIGS. 2b and 2 c) did not result in this effect. It is thus demonstrated that drug release rate, in addition to drug dosing, affects biological response.
  • [0022]
    Based on these results, a high weight fraction of paclitaxel (35% in a polymer carrier) is acceptable, but a preferred weight fraction of paclitaxel is less than about 35% for a 1.0 micrograms/mm2 dosage, more preferably up to about 25%.
  • [0023]
    Most preferably, dosing of approximately 1.0 micrograms/mm2 of paclitaxel in a polymer coating was found to yield superior safety and efficacy. Within this dose, the preferred weight fraction of paclitaxel in this particular polymer carrier is less than about 35%. Such a combination results in the release of less than about 60 micrograms of paclitaxel within ten days after implantation, and less than about 45 micrograms within two days. As the inventors have found that lower doses lead to preferred physiologic responses, it is preferred that the coating system result in the cumulative release of less than about 20 micrograms of paclitaxel ten days after implantation, more preferably less than 15 micrograms, more preferably less than 10 micrograms, more preferably less than 8 micrograms, more preferably less than 6 micrograms, and more preferably less than 4 micrograms. It is additionally preferred that less than 10 micrograms of paclitaxel be released two days after implantation, more preferably less than 5 micrograms, and more preferably less than 2 micrograms.
  • [0024]
    [0024]FIG. 2 also demonstrates a continual release of drug over prolonged time frames. All curves in FIG. 2 show a relatively rapid release rate over the first few days, followed by a slower, sustained release over up to about two weeks. The inventors have found that such release rate characteristics are preferred for efficacy. In particular, the inventors have found that a coating system resulting in drug release for a period of at least eight days, and more preferably ten days, is preferred. Also, the inventors have found that the period of rapid release rate is most effective if the maximum release rate is achieved during 1-3 days after implantation, more preferably during the second day after implantation.
  • [0025]
    Although most examples herein use a polymeric carrier to deliver paclitaxel from a coated stent, it is anticipated that the optimal dosing and release rates identified by the inventors would apply to drug coated stent systems in which no polymer carrier is used, such as where paclitaxel or another drug is applied directly to the stent in the absence of a polymer carrier.
  • [0026]
    In still other embodiments, the stent is a degradable polymer stent that contains the paclitaxel, rather than being made from a biostable material that is coated with drug.
  • [0027]
    Although the invention is described as being specific to paclitaxel, it should be recognized that the inventors' findings should be applicable to a wide variety of drug systems.
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Classifications
U.S. Classification424/423, 604/93.01, 514/449
International ClassificationA61F2/84, A61K31/337, A61P9/00, A61L31/16
Cooperative ClassificationA61L31/16
European ClassificationA61L31/16
Legal Events
DateCodeEventDescription
Nov 25, 2002ASAssignment
Owner name: SCIMED LIFE SYSTEMS, INC., MINNESOTA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BARRY, JAMES J.;KAMATH, KALPANA R.;REEL/FRAME:013548/0833;SIGNING DATES FROM 20021112 TO 20021114
Mar 18, 2005ASAssignment
Sep 18, 2008FPAYFee payment
Year of fee payment: 4
Oct 1, 2012FPAYFee payment
Year of fee payment: 8